U.S. patent number 6,434,409 [Application Number 09/588,231] was granted by the patent office on 2002-08-13 for determination of glucose concentration in tissue.
This patent grant is currently assigned to Roche Diagnostics GmbH. Invention is credited to Udo Hoss, Margret Pfeiffer.
United States Patent |
6,434,409 |
Pfeiffer , et al. |
August 13, 2002 |
Determination of glucose concentration in tissue
Abstract
The present invention concerns a method for determining and
monitoring tissue glucose concentration. Additionally, the present
invention concerns a measuring apparatus to determine and monitor
glucose concentration.
Inventors: |
Pfeiffer; Margret (Ulm,
DE), Hoss; Udo (Ulm, DE) |
Assignee: |
Roche Diagnostics GmbH
(Mannheim, DE)
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Family
ID: |
7793775 |
Appl.
No.: |
09/588,231 |
Filed: |
June 6, 2000 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
Issue Date |
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147207 |
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6091976 |
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Foreign Application Priority Data
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May 9, 1996 [DE] |
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196 18 597 |
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Current U.S.
Class: |
600/347; 600/345;
600/365; 600/366 |
Current CPC
Class: |
A61B
5/14528 (20130101); A61B 5/14532 (20130101); A61B
5/14865 (20130101); A61B 5/686 (20130101); A61B
5/7207 (20130101) |
Current International
Class: |
A61B
5/00 (20060101); G01N 33/487 (20060101); A61B
005/05 (); A61B 005/00 () |
Field of
Search: |
;600/347,345,348,352,354,365,366,368 |
References Cited
[Referenced By]
U.S. Patent Documents
Foreign Patent Documents
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41 30 742 |
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Mar 1993 |
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DE |
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44 01 400 |
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Jul 1995 |
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DE |
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44 26 694 |
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Feb 1996 |
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DE |
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0 256 415 |
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Feb 1988 |
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EP |
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Primary Examiner: Shaver; Kevin
Assistant Examiner: Natnithithadha; Navin
Attorney, Agent or Firm: Arent Fox Kintner Plotkin &
Kahn
Parent Case Text
CROSS REFERENCE TO RELATED APPLICATION
This application is a divisional application of U.S. application
Ser. No. 09/147,207, filed Oct. 28, 1998, which was filed as
PCT/EP101075 on Mar. 4, 1997, the disclosure is hereby incorporated
by reference.
Claims
What is claimed is:
1. Measuring apparatus to determine and monitor tissue glucose
concentration, comprising a microdialysis probe (12) implantable
into the tissue (10) and being loadable at its inlet side through a
perfusate line (21) with a perfusion solution (18) and being
connected at its outlet side through a dialysate line (22) to an
flow through test cell (14), and conveyor unit (26) mounted in the
perfusate or dialysate line to move the perfusion solution through
the microdialysis probe (12) to the test cell (14), characterized
by at least one reservoir (20) containing dissolved glucose in a
predetermined initial concentration and connected to the perfusate
line (21).
2. Measuring apparatus as claimed in claim 1, characterized by two
glucose reservoirs connected to the perfusate line and containing
dissolved glucose of a concentration different from that of the
other.
3. Measuring apparatus as claimed in claim 1, characterized in that
the at least one reservoir (20) containing glucose can be connected
through a switching valve to the perfusate line (21).
4. Measuring apparatus as claimed in claim 1, characterized in that
the conveyor unit is preferably a metering pump (26) which can be
operated in intermittent manner.
Description
FIELD OF THE INVENTION
The invention relates to a method and apparatus to determine and
monitor the concentration of tissue glucose as defined in the
preambles of the independent claims 1 and 17.
BACKGROUND OF THE INVENTION
Methods of this kind are applicable foremost in human medicine, in
particular to monitor the blood sugar of diabetics. They are based
on the insight that the glucose content of the interstitial tissue
fluid is highly correlated, with little time delay, to the blood
sugar level. It is known to recover glucose by dialysis and then to
determine the glucose content by enzymatic-amperometric
measurements in an flow-through test cell. For that purpose a
continuous flow of perfusate is made to pass along the dialysis
membrane of the dialysis probe. The yield so obtained depends
essentially on the rate of perfusion and as a rule is less than
30%. The measurement is commensurately inaccurate because
interfering factors such as tissue movement and changes in blood
circulation strongly affect the yield and hence the test signal.
Lowering the perfusion rate will not help because entailing a
correspondingly higher dead time caused by the flow time between
the microdialysis probe and the test site. On the other hand, high
rates of flow velocity do indeed lower the dead time. However the
dialysis yield relative to a unit volume of perfusion solution
decreases to the same extent. Moreover a glucose gradient is formed
in the tissue surrounding the microdialysis probe on account of
continuously withdrawing glucose. However long-term treatment of
diabetics mandates reliable glucose measurements to dose insulin
administrations as needed and, where desirable, automatically.
SUMMARY OF THE INVENTION
Based on the above, the objective of the invention is to create a
method and apparatus of the initially cited kinds which offer high
reliability and accuracy as regards glucose determination.
The combinations of features stated in the patent claims 1 and 17
are proposed as solutions. Further advantageous implementations of
the invention are stated in the dependent claims.
The conventional continuous enrichment of the perfusion solution is
replaced in the invention by equalizing the liquid column, moved in
segments with high yield through the microdialysis probe, and the
tissue glucose content. Accordingly the invention proposes to
reduce the time-averaged volumetric flow of the perfusion solution
for the duration of dialysis intervals and that the volume of
perfusion solution perfused during each dialysis interval through
the microdialysis probe shall be moved on in an ensuing transport
interval at a higher volumetric flow to the test cell. The
equalization of concentration taking place during the dialysis
intervals averts continuous impoverishment of the tissue. At the
same time, high signal strength is achieved because of the higher
yield. The enriched partial volumes can be moved at a higher
conveyance flow and thus with a lesser dead time to the test
cell.
In a preferred implementation of the invention, the perfusion
solution is mixed with glucose before being made to pass through
the microdialysis probe and a predetermined initial concentration
is set, preferably within the physiological range. Using an initial
solution mixed with glucose leads to diffusion enrichment or
impoverishment at the dialysis membrane depending on the tissue
glucose concentration. Accordingly a signal peak or a signal dip is
observed in the time-sequence of the test signals at the test cell.
On the other hand the subsequent perfusion solution passing at a
higher flow during the transport intervals through the
microdialysis probe essentially retains its initial glucose
concentration. Accordingly a base line reflecting the initial
glucose concentration is picked up during the subsequent flow
through the cell.
Advantageously the volumetric flow of perfusion solution is so
adjusted during the transport intervals that the glucose content of
the perfusion solution changes less than 10%, preferably less than
5%, on account of the reduced duration of dialysis, when passing
through the microdialysis probe. On the other hand, in order to
increase the accuracy of measurement, the volumetric flow during
the dialysis intervals should be adjusted in such manner that the
glucose content of the perfusion solution essentially matches the
concentration of tissue glucose when passing through the
microdialysis probe.
Advantageously a base line value is determined from the test
signals picked up at the test cell during the flow-through of the
volume of the perfusion solution perfused at higher-volumetric
flow, said base line value reflecting the initial glucose
concentration and thereby allowing continuous signal correction for
instance in the event of fluctuations in test sensitivity.
Advantageously the peak test signals ascertained during the
transport intervals at the test cell when crossed by the enriched
liquid-column segments are evaluated with respect to their extreme
value, hereafter called extremum/extrema, or of their integrated
value, to determine the tissue glucose concentration.
Advantageously the tissue glucose concentration is determined in
each transport interval from the ratio of the extremum to the base
line value of the test signal multiplied by the value of initial
glucose concentration and where called for by a predetermined
calibration value. This procedure allows constantly updated
calibration of the glucose test values and compensating any signal
drifts. In this manner spurious measurements can be precluded that
otherwise might arise from conveyance malfunctions or interferences
in the test cell.
Because of the peak-shaped signal sequence of the test signals,
validity testing is feasible in that the predetermined time between
the extrema of the test signals will be monitored by the time
between the transport intervals.
Advantageously again, the signal sequence of the test signals is
used for validity-checking the ascertained glucose content, a peak
being expected as a valid signal shape when comparing a
concentration value higher than the initially set glucose
concentration and a dip for a lesser value of concentration. In
this manner reliable, qualitative checking of the measurements is
possible. Another increase in reliability of measurement can be
achieved in that the initial glucose concentration is set to a
sugar deficiency value and in that when the test signals undergo a
dip in their sequence, a sugar-deficiency alarm is triggered.
Moreover it is basically feasible to adjust the initial glucose
concentration in phases alternatingly--for instance using a valve
circuit--to a sugar deficiency value and an excess sugar value, an
alarm signal being emitted at a dip during the phase of adjusted
sugar deficiency value and at a peak during the phase of adjusted
excess sugar value.
Qualitative pattern recognition in the sequence of the test signals
is implemented in simple manner in that the extrema ascertained in
the time between the transport intervals are compared with the
particular associated base line value, where a peak shall be
recognized when comparing an extremum larger than the base line
value and a dip shall be recognized when comparing an extremum
smaller than the base line value.
In another preferred implementation of the invention, the perfusion
solution is moved during the dialysis intervals always in several,
time-separated conveyed batches through the microdialysis probe.
Thereby the glucose-enriched segment of the liquid column is
widened and correspondingly the diffusion decay will be reduced
during the ensuing transport interval.
When seeking high yield in the dialysis, advantageously a volume of
the perfusion solution substantially corresponding to the volume of
the microdialysis probe is moved at each conveyed batch. Another
improvement can be achieved in this respect by so sizing the
conveyance pauses between conveyed batches that the glucose content
of the perfusion-solution volume instantaneously present in the
microdialysis probe shall substantially equal the tissue glucose
concentration.
In an alternative to the batch-conveyance, the volumetric flow of
the perfusion solution may be reduced to a constant value for the
duration of the dialysis intervals.
The initially cited problem regarding the measurement apparatus is
solved in that at least one glucose reservoir containing glucose in
a predetermined initial concentration can be connected to the
perfusate line. In order to ascertain whether the tissue glucose
represents a deficiency or excess of sugar, two glucose reservoirs
separately connectable to the perfusate line may be used, each
containing dissolved glucose of a different concentration.
Advantageously the at least one glucose reservoir shall be
connectable through a switching valve to the perfusate line to
allow mixing the perfusion solution selectively at separate times
and/or if called for at a different concentration to the perfusate
line.
A defined batch-wise conveyance of the perfusion solution, which
may be enriched with glucose, can be implemented by using a
metering pump preferably operated at intervals as the conveyor
unit.
BRIEF DESCRIPTION OF THE DRAWINGS
The invention is elucidated below in relation to an illustrative
embodiment which is schematically shown in the drawing.
FIG. 1 shows a microdialysis system to measure subcutaneous glucose
concentration, and
FIG. 2 is a time plot of the volumetric flow of the perfusion
solution through the system of FIG. 1.
DETAILED DESCRIPTION OF THE DRAWINGS
The method of the invention to subcutaneously measure tissue
glucose is based on the principle of microdialysis and can be
carried out using the measuring apparatus shown in FIG. 1.
Essentially this measuring apparatus consists of a microdialysis
probe 12 implantable into the patient's subcutaneous fatty tissue
10, of an through-flow test cell 14 located outside the patient's
body and a signal-processing unit 16 cooperating with the test cell
14. To withdraw a sample from the tissue 10, a perfusion solution
18 is pumped out of a reservoir 20 through a perfusate line 21 as a
continuous column of liquid while passing through the microdialysis
probe 12 and by means of a connecting line 22 through the test cell
14 into a collecting vessel 24. This pumping is implemented by a
two-channel roller metering pump 26 inserted into the connecting
line 22. The second channel of the roller metering pump 26 is
loaded at its intake side through a line 28 with an enzyme solution
30 which is fed at its outlet side at a mixing station 32 into the
connecting line 22.
When the perfusion solution 18 flows through the microdialysis
probe 12, a glucose diffusion exchange takes place at the
glucose-permeable dialysis membrane 34 between the perfusion liquid
and the tissue liquid. Depending on the concentration gradient, the
perfusion solution 18 flowing past the membrane 14 is enriched with
tissue glucose. Thereupon the glucose content of the perfusion
solution is determined in known manner, using an
electrochemical/amperometric sensor, in the test cell 14, as an
electrode signal and is analyzed in the signal processing unit 16.
The basic detection reactions catalyzed by the enzyme solution 30
are described in detail in the German Offenlegungsschrift 44 01
400, and are explicitly referred to herewith. In an alternative,
the glucose also may be detected using an enzyme sensor as
described in the German Offenlegungsschrift 41 30 742.
The conveyance of the perfusion solution 18 through the pump 26 is
carried out in the invention at predetermined time intervals in the
manner shown in FIG. 2. The perfusion solution is moved during a
dialysis interval T.sub.1 at several mutually distinct and
consecutive times in conveyed batches 36, each conveyed batch 36
corresponding substantially to the volumetric content of the
microdialysis probe 12. The conveyance pauses 38 between the
conveyed batches 36 are selected in such manner that the glucose
content of the particular volume of perfusion solution 18 in the
microdialysis probe 12 substantially equals the tissue glucose
concentration. In principle the volumetric flow of the perfusion
solution 18 also may be reduced to a constant value dV.sub.0 /dt
for the duration of the dialysis interval, whereby the transmitted
quantity of perfusion solution 18 during the time interval T.sub.1
corresponds to that of the batch conveyance. However the pump 26
then must be adjustable in its flow.
The volume of perfusion solution 18 enriched in the probe 12 during
the interval T.sub.1 is pumped during the course of the ensuing
transport interval T.sub.2 at a constant volumetric flow dV.sub.1
/dt determined by the flow output of the pump 26 into the test cell
14. On account of the higher speed of flow, the trailing perfusion
solution 18 flowing in this phase through the microdialysis probe
12 is hardly laden with glucose from the tissue 10. Therefore the
test signal from the test cell presents a peak value when the
enriched segments of the liquid column are moved past and it will
show a base line value when liquid volumes passing through the
probe 12 with short durations of perfusion are being transported.
Accordingly the base lines and the extrema can be measured at
predetermined times within the total time interval T.sub.1
+T.sub.2. Typical conveyance flows are 0.3-1 .mu.ltr/min for
T.sub.1 and 5-50 .mu.ltr/min for T.sub.2.
Improved analysis, in particular regarding signal drift and
validity, is implemented in that the perfusion solution 18 in the
reservoir 20 is mixed with glucose. The initial concentration
within the physiological range is set for instance at 5 mmole/ltr.
Alternatively however, the glucose solution can be prepared
separately from the perfusion solution 20 in separate glucose
reservoirs appropriately and selectively communicating through
switching valves with the perfusate line 21.
If the test sensor is linear, tissue glucose can be ascertained by
the fact that the ratio of the extremum detected during the
interval to the associated base line value is multiplied by the
value of the initial glucose concentration and where called for by
a calibration factor. The calibration factor can be determined by a
one-time in-vivo comparison measurement of the glucose levels in
the blood and in the tissue. Appropriately an offset ascertained by
a one-time in-vitro measurement before implantation while dipping
the probe 12 into a glucose-free test solution shall be taken into
account. Adding glucose to the perfusion solution 18 therefore
allows automatically recalibrating the test signals once an initial
calibration was carried out.
Signal validity can be monitored merely by pattern recognition. A
peak is obtained when comparing a glucose content of the tissue 10
which is higher than the adjusted concentration, and a dip if the
glucose content is lower. Illustratively a signal shape which
deviates because of zero shift can be detected in this manner as
being invalid. In this manner it is possible also to monitor a
patient's glucose level within a predetermined range by means of
simple qualitative comparison measurements. For instance the
initial glucose concentration in the perfusion solution 30 may be
alternatingly adjusted to a sugar-deficiency value and to an excess
sugar value, a warning signal being emitted for a dip in the
sequence of the test signals during the phase adjusted
sugar-deficiency concentration and for a peak during the phase of
adjusted sugar-surplus concentration.
In this procedure, signal shape recognition is restricted to
detecting two measurement values in each case, namely an extremum
associated with the high glucose yield during the dialysis interval
T.sub.1 and a base line value associated with the low glucose yield
(because of the high volumetric flow dV.sub.1 /dt) during the
transport intervals T.sub.2. The two measurement values can be
ascertained each at predetermined times within the time interval
T.sub.1 +T.sub.2, a peak being assumed as the signal shape when
comparing an extremum larger than the base line value, and a dip
being assumed when comparing an extremum smaller than the base line
value.
In summary, the invention relates to a method and apparatus for
determining tissue glucose, a perfusion solution being moved as a
liquid column to pass through a microdialysis probe implanted in
the tissue to a test cell. In order to increase yield, to avert
concentration gradients and to reduce the dead time, the invention
proposes that the volumetric flow V of the perfusion solution over
the duration of the dialysis intervals T.sub.1 be reduced to a
time-averaged value of dV.sub.0 /dt and that the volume of the
perfusion solution which is perfused through the microdialysis
probe during each dialysis interval T.sub.1 be moved in each
ensuing transport interval T.sub.2 at a higher volumetric flow
dV.sub.1 /dt to the test cell.
* * * * *